Background To determine whether the reduced exercise capacity of patients after heart transplantation is primarily a result of decreased cardiac or peripheral vascular factors, we examined the cardiac output (CO) and right atrial pressure (Pra) relation during graded cycle ergometry. Methods and Results We studied 12 male patients (51.2 ± 15.3 years [mean ± SD]) 35.3 ± 12.5 weeks after heart transplantation and 6 young healthy men. Patients had a normal increase in CO with increasing oxygen uptake ( v̇O₂) (CO = 0.00597 v̇O₂ + 4.4, r = 0.83). Mean (± SEM) heart rate increased from 97.0 ± 5.0 beats/min at rest to 146.9 ± 6.9 beats/min at peak effort compared with the increase of 67.2 ± 1.9 beats/min to 187.2 ± 2.5 beats/min in the normal group. Pra in patients increased from 1.6 ± 1.0 mm Hg at rest to 8.9 ± 1.6 mm Hg during mild exercise but did not increase further at the highest work rates, even though CO continued to increase. In the normal group there was an initial increase in Pra from rest to exercise transition but little further change in Pra with increasing CO. Aerobic capacity (peak v̇O₂) did not increase when cardiac function was increased with dobutamine during exercise in two patients. Conclusions The steep increase in CO relative to Pra during severe exercise in patients who undergo heart transplantation argues against the heart as the sole limiting factor during maximal effort. (Am Heart J 1998;135:339-48.)